Drug withdrawal periods

Differences in MRL/tolerances more often reflect differences in the use of that compound in a particular country, or in the choice of safety factors, food consumption values, or the analyte used in monitoring programs. The United States will, but does not always, assign tolerances when preslaughter drug withdrawal period is zero. Generally, the European Union assigns an MRL even when withdrawal periods are not required. 

Table 2 Examples of drugs and period of withdrawal from animals prior to use as food ...

Produce from trial animals may not enter the food chain unless authorised by the CVM on the basis of data showing that residues will be either safe or not present in produce from animals treated at the maximum dosage with the minimum allowed withdrawal period. The CVM must be notified of the date and place of slaughter at least 10 days prior to each shipment for slaughter. The regulations also address the retention of records and the competence of study investigators. Records of drug shipments must be maintained for at least 2 years after the date of shipment. Data and results of trials must be retained for either 2 years after completion of the trial, or... 

Supporting this conclusion is the fact that approval times have decreased from 27 to 14 months. However, the GAO also reported a small increase in the drug-withdrawal rate since the implementation of PDUFA. That is, a higher percent of approved drugs has been withdrawn from the market because of safety issues. FDA officials argue that the increase is insignificant - from 3.10% in the 8-year period before PDUFA to 3.47% in the 8-year period after. 

Certain of the chemotherapeutics. for example the sulfa drugs, have been of greater concern from the point of view of tissue residues. Though there is no evidence that the sulfa residues found in pork livers or kidneys has or would cause human health problems, they are violative by our present standards. Therapeutic use (high dosages) of antibiotics are more likely to result in residues than are feed additive uses, but it is important that only approved levels and required withdrawal periods be adhered to for all drugs. 

Gradual withdrawal - Periodically attempt to reduce dosage to see if tics persist. Increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than a return of symptoms. Allow 1 or 2 weeks to elapse before concluding that an increase in tic manifestations is caused by the underlying disease rather than drug withdrawal. A gradual withdrawal is recommended in any case. 

Even after relatively short periods of administration, discontinuation of short and intermediate half-life BZDs, such as triazolam and temazepam, may result in marked worsening of sleep, even worse than baseline levels (i.e., rebound insomnia), although this does not seem to occur with zolpidem (95, 102, 103, 109, 110, 113, 285, 297, 316, 325, 326, 327, 328, 329, 330, 331,332, 333, 334, 335, 336 and 337). Gradual dose reduction may attenuate the incidence of rebound, and with flurazepam and quazepam, little sleep disturbance occurs, even after abrupt drug withdrawal ( 99, 100, 101, 102, 103,104, 105 and 106, 280, 338, 339, 340 and 341). 

The major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias. Potassium, magnesium, and phosphate balance should be restored as rapidly as is consistent with renal function. Thiamine therapy is initiated in all cases. Persons in mild alcohol withdrawal do not need any other pharmacologic assistance. 

In principle, all drug preparations administered to food-producing animals may lead to residues in the edible tissues, milk, or eggs. In addition to the drug dosage, the levels of those residues depend on the period between administration and slaughter or collection of the animal products, the so-called withdrawal period, which, on its turn, depends on the pharmacokinetic profile of the drug. 

Bambermycin is an antibiotic that, because of its heteropolar behavior, tends to form complexes. It is, therefore, a compound that is extremely difficult for animals to absorb. Balance studies proved that bambermycin is not absorbed but is excreted in the feces as tire intact, biologically active drug. As a result, no withdrawal period is required. 

Unfortunately, streptomycin residues persist for long time at the site of injection and are also found in the kidney. Residue levels in other edible products of drug-treated sheep, pigs, and poultry were generally low and did not necessitate long withdrawal periods. 

Following intramuscular injection of chloramphenicol in sheep, the withdrawal period down to the level of 0.05 ppm was estimated at 14.4 days for the injection site, 6 days for noninjected muscle, 9 days for fat, 11 days for kidney, and 11 days for the liver (32). When chloramphenicol was administered to rabbits, muscle and kidney were the tissues containing the highest levels of the parent drug at 6 h postdosing, whereas at 24 h only muscle contained detectable amounts of residues (33). 

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